Colorimetric methods based on the Berthelot reaction are used widely for quantitative determination of NH4‐N in biological and environmental samples. Studies to evaluate phenol and salicylate, the most commonly used chromogenic substrates, revealed minor interferences by metallic cations, whereas up to a threefold shift in absorbance was observed with 38 diverse N‐containing organic compounds. Interferences differed markedly between phenol and salicylate. The possibility of a simple correction was precluded by the fact that interferences were both positive and negative, and depended on the temperature during color development and the concentration of NH4‐N. Fourteen compounds were evaluated as alternatives to phenol and salicylate, of which the Na salt of 2‐phenylphenol (PPS) proved to be the most promising. Using PPS, macro‐ and microscale batch methods and an automated flow‐injection method were developed. These methods are simple, convenient, and sensitive. Using the PPS microscale method, for which the limit of detection is 0.17 mg NH4‐N L−1, recovery of NH4‐N added to soil extracts ranged from 98 to 104%, with a coefficient of variation of 1.4 to 2.7%. As with phenol and salicylate, precipitation of metal hydroxides was observed. Precipitation was controlled by chelation with citrate rather than ethylenediaminetetraacetic acid (EDTA), which suppressed color development by preventing monochloramine formation. Compared with Berthelot methods that use phenol or salicylate, interference by amino acids was decreased by up to 10‐fold. Interference by other organic N compounds was virtually eliminated.

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The finding of no difference in insulin sensitivity between the two groups contrasts with, but does not entirely contradict, the results of previous epidemiological studies--perhaps suggesting that longer term changes such as liver enzyme induction may be important. The difference in insulin secretion questions the validity of previous studies of the influence of alcohol on insulin sensitivity, where insulin levels were used as a surrogate for insulin resistance.

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The G protein-coupled receptor 40 (GPR40) also known as free fatty acid receptor 1 (FFAR1) is highly expressed in pancreatic, islet β-cells and responds to endogenous fatty acids, resulting in amplification of insulin secretion only in the presence of elevated glucose levels. Hypothesis driven structural modifications to endogenous FFAs, focused on breaking planarity and reducing lipophilicity, led to the identification of spiropiperidine and tetrahydroquinoline acid derivatives as GPR40 agonists with unique pharmacology, selectivity, and pharmacokinetic properties. Compounds 1 (LY2881835), 2 (LY2922083), and 3 (LY2922470) demonstrated potent, efficacious, and durable dose-dependent reductions in glucose levels along with significant increases in insulin and GLP-1 secretion during preclinical testing. A clinical study with 3 administered to subjects with T2DM provided proof of concept of 3 as a potential glucose-lowering therapy. This manuscript summarizes the scientific rationale, medicinal chemistry, preclinical, and early development data of this new class of GPR40 agonists.

Aim: To assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of basal insulin Fc (BIF; LY3209590), a fusion protein combining a novel singlechain insulin variant together with human IgG2 Fc domain, following single and multiple once-weekly BIF administration. Materials and Methods:The single ascending dose, 15-day study assessed four BIF doses (5-35 mg) in healthy participants and people with type 2 diabetes (T2D). In the 6-week multiple ascending dose study, people with T2D, previously treated with basal insulin, received insulin glargine daily or a one-time loading dose of BIF followed by 5 weeks of once-weekly dosing (1-10 mg). Safety, tolerability and PK and glucose PD were examined.Results: Mean ages of people with T2D (N = 57) and healthy participants (N = 16) in the single-dose study were 58.4 and 35.8 years, respectively; mean body mass index values were 29.5 and 26.1 kg/m 2 . BIF had a PK half-life of approximately 17 days, which led to a sustained, dose-dependent decrease in fasting blood glucose for 5 days or longer. No severe hypoglycaemia was observed. The 6-week ascending dose study included 33 people with T2D aged 40-69 years. BIF showed a low peakto-trough ratio of 1.14 after the last dose at week 6 (steady state). Over 6 weeks, BIF seven-point glucose profiles remained constant and were similar to insulin glargine.Rates and duration of BIF hypoglycaemic events were similar to insulin glargine.Conclusions: BIF was well tolerated and the PK/PD profile enabled once-weekly dosing with minimal variation in exposure in a treatment interval of 1 week. The findings suggest BIF is suitable for further development as a weekly basal insulin in people with diabetes.

OBJECTIVE To evaluate the effects of tirzepatide on body composition, appetite, and energy intake to address the potential mechanisms involved in body weight loss with tirzepatide. RESEARCH DESIGN AND METHODS In a secondary analysis of a randomized, double-blind, parallel-arm study, the effects of tirzepatide 15 mg (N = 45), semaglutide 1 mg (N = 44), and placebo (N = 28) on body weight and composition, appetite, and energy intake were assessed at baseline and week 28. RESULTS Tirzepatide treatment demonstrated significant reductions in body weight compared with placebo and semaglutide, resulting in greater fat mass reduction. Tirzepatide and semaglutide significantly reduced appetite versus placebo. Appetite scores and energy intake reductions did not differ between tirzepatide and semaglutide. CONCLUSIONS Differences in energy intake during ad libitum lunch were not sufficient to explain the different weight outcomes. Further evaluation is needed to assess mechanistic differences related to tirzepatide actions on 24-h energy intake, substrate utilization, and energy expenditure.

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